This proposal will investigate the basis of the antiproliferative activity of opioids on two hormone dependent human breast cancer cell lines, T47D and MCF7. This investigation will encompass assessing the effects on proliferation of a series of receptor selective agonists and antagonists, determination of the degree of reversal of this phenomenon, and examination of the opioid receptor profile of these cell lines. Additional studies will be performed using alpha sl casomorphin, an opioid-like peptide derived form human alpha s1 casein as a lead peptide. Several series of analogues of the parent peptide and its amide derivative will be synthesized to explore the basis of this antiproliferative activity. These analogues will be screened for antiproliferative activity in T47D and MCF7 cell lines. If antiproliferative activity is observed, its basis will be explored using receptor selective antagonists. The peptides with the greatest antiproliferative effect will be additionally evaluated for opioid receptor affinity and agonist/antagonist opioid activity using either Chinese Hamster Ovary cells expressing cloned mu, kappa or delta opioid receptors or T47D and MCF7 cells in the presence of blocking agents.